Journal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
Volume 142, Issue 24, Pages 10869-10880Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jacs.0c01622
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Funding
- European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant [675007, 702574]
- EPSRC
- FCT Portugal [IF/00624/2015, CEECIND/02335/2017, LISBOA-01-0145-FEDER-022170, FCT-PTDC/MEC-ONC/31627/2017]
- CNPq [140485/2017-1, 311963/2017-0]
- Champalimaud Foundation
- Congento
- H2020 (EU_FT-ICR_MS) [GA 731077]
- CAPES [88887.310560-00]
- European Research Council [GA 676832]
- Royal Society University Research Fellow [URF\R\180019]
- Marie Curie Actions (MSCA) [702574] Funding Source: Marie Curie Actions (MSCA)
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The ability to create ways to control drug activation at specific tissues while sparing healthy tissues remains a major challenge. The administration of exogenous target-specific triggers offers the potential for traceless release of active drugs on tumor sites from antibody-drug conjugates (ADCs) and caged prodrugs. We have developed a metal-mediated bond-cleavage reaction that uses platinum complexes [K2PtCl4 or Cisplatin (CisPt)] for drug activation. Key to the success of the reaction is a water-promoted activation process that triggers the reactivity of the platinum complexes. Under these conditions, the decaging of pentynoyl tertiary amides and N-propargyls occurs rapidly in aqueous systems. In cells, the protected analogues of cytotoxic drugs 5-fluorouracil (5-FU) and monomethyl auristatin E (MMAE) are partially activated by nontoxic amounts of platinum salts. Additionally, a noninternalizing ADC built with a pentynoyl traceless linker that features a tertiary amide protected MMAE was also decaged in the presence of platinum salts for extracellular drug release in cancer cells. Finally, CisPt-mediated prodrug activation of a propargyl derivative of 5-FU was shown in a colorectal zebrafish xenograft model that led to significant reductions in tumor size. Overall, our results reveal a new metal-based cleavable reaction that expands the application of platinum complexes beyond those in catalysis and cancer therapy.
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